title: Structure-activity study in the class of 6-(3'-hydroxyphenyl)naphthalenes leading to an optimization of a pharmacophore model for 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitors.
abstract: 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyzes the transformation of estrone (E1) into the most potent estrogen, estradiol (E2), which stimulates cell proliferation and decreases apoptosis. 17beta-HSD1 is often strongly overexpressed in estrogen-dependent diseases (like breast cancer and endometriosis). Thus, this over expressed enzyme is a promising novel target for the development of selective inhibitors, which could be used as drugs for the treatment of these diseases. Using a structure- and ligand-based approach, a pharmacophore model was proposed and a new class of non-steroidal inhibitors of 17beta-HSD1 was designed. Enzyme inhibition was evaluated in vitro using the human enzyme. After identification of the 6-(3'-hydroxyphenyl)-2-naphthol scaffold 1, the potency of this class of inhibitors was further improved by substitution of the 1-position of the naphthalene ring by a phenyl group (compound 18, IC(50)=20nM). Compound 18 also showed a good selectivity toward 17beta-HSD2 and the estrogen receptors alpha and beta.
authors.affiliation: 8.2 Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 15 11 50, D-66041 Saarbrücken, Germany.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
authors.forename: Martin
authors.initials: M
authors.lastname: Frotscher
authors.forename: Erika
authors.initials: E
authors.lastname: Ziegler
authors.forename: Ruth
authors.initials: R
authors.lastname: Werth
authors.forename: Patricia
authors.initials: P
authors.lastname: Kruchten
authors.forename: Josef
authors.initials: J
authors.lastname: Messinger
authors.forename: Hubert
authors.initials: H
authors.lastname: Thole
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D009281:Naphthalenes; C031721:naphthalene; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human